The interplay between the microbiota and opioid in the treatment of neuropathic pain

Abstract

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Keywords: gut microbiota; gut-brain axis; neuropathic pain; opioids; pain.

Figure 1

The involvement of gut microbiota in the gut-brain axis. The bidirectional communication between the gut microbiota and the brain occurs through endocrine (cortisol), immune (cytokines) and neural (vagus nerve and enteric nervous system) mechanisms (Josefowicz et al., 2012; Zhang et al., 2016; Cussotto et al., 2018; Russo et al., 2018; Guo et al., 2019; Ding et al., 2021; Dora et al., 2021; Ma et al., 2022; Araldi et al., 2023).

Figure 2

Utilizing gut microbiota and their metabolites to alleviate neuropathic pain through the neuroimmune system. (A) FMT reduces SCFAs, inhibiting the transformation of M1-like macrophages and promoting the increase of M2-like macrophages, ultimately relieving neuropathic pain. (B) Gut microbiota itself can promote the generation of bile acids, activate opioid receptors, and alleviate pain. (C) Some gut microbiota can increase the number of M2-like macrophages by inhibiting the production of SCFAs. (D). ABX alleviate pain by reducing the activation of Toll-like receptors in LPS-mediated M1-like macrophages and microglia. (E) ABX can also improve pain by altering gut microbiota and regulating regulatory T cells. FMT, fecal microbiota transplantation. SCFAs, short-chain fatty acids. ABX, antibiotics. LPS, lipopolysaccharides (Reichenberger et al., 2013; Van Laar et al., 2019; Bonomo et al., 2020; Cuozzo et al., 2021; Fonseca-Rodrigues et al., 2021; Jing et al., 2021; Lian et al., 2021; Wang et al., 2021; Ma et al., 2022).

Figure 3

Opioid-induced gut microbiota dysbiosis. The long-term effects of opioid treatment on the intestines are: (A) Directly weakening gastrointestinal motility, commonly resulting in complications such as constipation. Changes in intestinal motility and transit time further alter the composition of the intestinal microbiota and cause translocation of gut microbiota. (B) Directly altering the composition and dysbiosis of the intestinal microbiota, such as a decrease in Lactobacillus and Bifidobacterium, an increase in Staphylococcus and Enterobacter, and potentially increasing other pathogenic bacteria. (C) Damage to the intestinal epithelial barrier (increased permeability, disruption of tight junction proteins, decreased immune function). The dysregulation of intestinal microbiota and function ultimately affects systemic inflammation and contributes to the development of opioid resistance via the gut-brain axis (Acharya et al., 2017; Bhave et al., 2017; Guo et al., 2019; Zhang et al., 2019a).